Study of Two Cholesterol Drugs Finds One Halts Heart Disease

The first study to compare two powerful cholesterol-lowering drugs head-to-head in coronary artery disease finds that one appears to be superior.

In patients taking pravastatin, or Pravachol, made by Bristol-Myers Squibb, atherosclerosis worsened slowly over 18 months. But the disease was halted in those who took the highest dose of atorvastatin, or Lipitor, the drug made by Pfizer.

''We saw something extraordinary,'' said Dr. Steven Nissen, the cardiologist at the Cleveland Clinic who directed the study of 502 patients.

''All statins are not alike,'' Dr. Nissen said, adding that with pravastatin, heart atherosclerosis will worsen, but with the highest dose of atorvastatin, that is unlikely.

At the study's start, the middle-aged, mostly male heart disease patients in the study had levels of low density lipoproteins, or L.D.L., of 150, on average. L.D.L. carries cholesterol to arteries. Atorvastatin lowered participants' L.D.L. levels to 79, while those taking pravastatin had an average level of 110.

After 18 months, the atorvastatin patients had no change in the plaque in their arteries. But plaque increased by 2.7 percent in pravastatin patients. The study did not assess patient outcomes like heart attacks and deaths, which would have required 8,000 patients and taken five or more years.

Pfizer sponsored the study, but Dr. Nissen, who prides himself on his independence from financial conflicts of interest, insisted that he control the study and its data analysis, and had the right by contract to publish the results whether positive or negative for Pfizer. He described the results yesterday at the American Heart Association meeting in Orlando, Fla., and submitted a paper for publication.

''A lot of people thought all statins were the same,'' he said in a telephone interview.

If the two statins had turned out to be about equal, Pfizer might have lost in the multibillion-dollar statin market because pravastatin is nearing the end of its patent life and generic versions should be cheaper.

''Pfizer could have lost big time,'' Dr. Nissen said. When the results were in, and the company was waiting to hear what they were, ''I never saw such nervousness,'' he said.

Dr. Gary Palmer, the vice president of Pfizer's cardiovascular medicine group in the United States, said the company was very excited. ''For the first time, we've actually shown that you can impact the progress of this disease, which is the leading cause of death in the United States,'' Dr. Palmer said.

But Julie Keenan, a spokeswoman for Bristol-Myers Squibb, noted that the study just looked at plaque, not at heart attacks or deaths.

''While these results are informative,'' Ms. Keenan said, ''additional studies will be needed to assess whether different statins would cause disparate reductions in clinical outcomes.''

Pravastatin has been shown to prevent heart attacks in people with high cholesterol levels, she added.

Cardiologists say the study addresses a question that plagues them: How low should cholesterol go? National guidelines call for lowering L.D.L. levels in heart disease patients to less than 100 milligrams per deciliter of blood. But, said Dr. Daniel Rader, a lipid researcher at the University of Pennsylvania, ''one of the big issues is, 'Is that enough?' '' And, he added, ''Where do you stop?''

And what about people with high cholesterol levels who have not had a heart attack or other manifestation of heart disease? Should they, too, go for maximum L.D.L. lowering? What if the only risk factor is a high level of L.D.L.? Current guidelines suggest less aggressive L.D.L. lowering for people at lower risk.

''There's a certain inconsistency,'' Dr. Rader said. ''If you are trying to reduce risk, once you make decision to put someone on a drug, why not target the same level for everyone?''

Medical experts said national guidelines were unlikely to be changed until additional studies found that more aggressive cholesterol lowering resulted in a reduced risk of heart attacks and death.

The study assessed the progression of atherosclerosis using a tiny ultrasound camera that was threaded into coronary arteries, allowing researchers to look directly at the growth of plaque. Large studies are under way seeking to determine if more growth, as detected by the ultrasound camera, means more heart attacks and deaths, but many cardiologists predict that it does. ''The probability is very high,'' said Dr. Bryan Brewer, chief of the molecular diseases branch at the National Heart, Lung and Blood Institute.

Researchers say they only recently came to understand how plaque in artery walls can kill. They used to think that the danger period was when the tumorlike plaque narrowed arteries. Now, said Dr. Peter Libby, the chief of cardiovascular medicine at the Brigham and Women's Hospital in Boston, they realize that the danger occurs long before that.

At first, plaque grows from the inner wall of the artery out, Dr. Libby said, making the artery thicker but not narrower. Only at the very end of this process does the plaque start to grow inward, narrowing the artery. But most fatal heart attacks, Dr. Libby said, occur when one of the earlier-stage plaques pops open. Blood pours out, clots, obstructs the artery, and a heart attack ensues.

''The blood clot forms where the plaque opens,'' Dr. Libby said. ''It's revolutionized the way we look at the disease.'' The idea of looking at heart disease by looking at the diameter of an artery, he added, ''is like trying to learn about a doughnut by looking at the hole.''

Dr. Brewer said, ''You can get enormous changes in vessel wall pathology and little change in the lumen, the vessel diameter.'' That is why measuring the volume of plaque in artery walls can be so important to observing the progress of heart disease, he added.

But if the new study is correct, cardiologists and patients will be faced with difficult questions.

Pravastatin patients in the study whose L.D.L. levels fell below 100 still had plaque growth while atorvastatin patients with those L.D.L. levels did not.

Asked whether doctors should switch patients from pravastatin to atorvastatin on the basis of the findings, Dr. Nissen replied: ''I am going to choose to not answer that question. I will let my colleagues look at our findings and make their own minds up. I have already interpreted the findings and changed some of my practices.''

If atorvastatin is good, might more powerful drugs be even better?

A new drug, rosuvastatin, or Crestor, made by Astra Zeneca, can lower L.D.L. levels more than atorvastatin. When statins are combined with another type of drug, ezetimibe, or Zetia, made by Merck, the combination lowers L.D.L. even more. Why not go for the greatest lowering, if a person is at high risk?

''In fact, there's an opportunity to get very, very low,'' said Dr. Christie M. Ballantyne, a cardiologist at Baylor College of Medicine. ''Can we be reducing L.D.L. by 50 percent routinely? The answer is yes. What we still don't know is, is it O.K.? What will that mean in terms of costs of drugs, side effects of drugs, prevention of heart attacks?''

''This study is a proof of concept,'' Dr. Ballantyne said. ''As compared to cancer, we can stop this disease process in a fairly predictable way and prevent most heart attacks from ever happening.''

Correction: November 20, 2003, Thursday A front-page article last Thursday about a study comparing two of the cholesterol-lowering drugs known as statins referred incompletely to the manufacturer of a third drug, Zetia, which helps prevent the body from absorbing cholesterol. It is made by Merck & Company not alone but in a joint venture with the Schering-Plough Corporation. Correction: November 25, 2003, Tuesday A front-page article on Nov. 13 about a study of the cholesterol-lowering drugs Lipitor and Pravachol referred imprecisely to the directness of the comparison between them. While the study was a head-to-head comparison -- that is, both drugs were given to heart patients at the maximum allowable dose -- the article omitted those dosages. Patients on Lipitor, or atorvastatin, were given 80 milligrams a day. Patients on Pravachol, or pravastatin, were given half that dose, 40 milligrams a day, because that was the maximum allowable dose at the time. (Bristol-Myers Squibb, the maker of Pravachol, has since received approval for an 80-milligram dose.) The research, conducted by the Cleveland Clinic and financed by Pfizer, the maker of Lipitor, was intended to test the effects of aggressive and moderate therapies on lowering cholesterol. (In an 18-month period, the Lipitor patients reduced their low density lipoprotein levels -- L.D.L.'s -- from 150 on average to 79. The levels for Pravachol patients fell to an average of 110. Plaque growth stopped in those taking Lipitor; it increased 2.7 percent in those on Pravachol after 18 months. Both drugs are known to prevent fatal heart attacks.)